GDP and Integrity of The Supply Chain

Presented by: Karen S Ginsbury

B.Pharm, MSc, MRPharmS

For: IFF, October 2010

What are the Risks

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What are the Risks in GDP?

• For a formal assessment need to use one

of the tools in ICH Q9 / Annex 20:

– HACCP

– FMEA

– Ishikawa (Fishbone) diagram + one of the

other methods

• Will take you to a lot of the points already

mentioned

Every Picture Tells a Story

Distributors, Wholesalers, Importers,

Exporters, Pharma companies

ONE CALL STARTS THE PROCESS

CONTAINER RENTAL (DRY ICE & BATTERIES)

PICKUP AT AIRLINE

CUSTOMS CLEARANCE IN EUROPE, CLEAR THE CARGO WHILE STILL IN-

FLIGHT

CONTAINER LOADED, TEMPERATURE SET,

CONTAINER SEALED AND IMMEDIATELY TAKEN TO

AIRPORT

CUSTOMER CALL

PROCESS INITIATION

NON-STOP FLIGHT

ENROUTE TO CONSIGNEE

ARRIVAL AT CONSIGNEE LOCATION

ENROUTE

To be discussed...

• Regulations:– EU directive– WHO Guideline– EU concept paper for updating

• Scope of the regulations• Quality Management System• Quality Agreements with customers• Personnel Requirements: training and qualification• Premises and Equipment• Documentation• Repackaging / Re-labeling controls• Quality Control

To be discussed...

• Warehousing and temperature control

• Qualification and Validation of GDP activities, with a very brief look at computerized systems

• Picking goods / preparing orders, FiFo vs FeFo

• Controls and documentation

• Managing a controlled temperature vehicle fleet

• Contractors: cars / trucks; printers for packaging materials; maintenance, calibration and qualification of equipment

• The role of the QP

• Deviations and Change Control

• Returned Goods, Complaints and Product Recall

• Auditing – of your company by customers and of your sub-contractors and vendors

•C

ounte

rfeit M

edic

ines

MHRA Press ReleaseDate:05 Nov 2007

Time:15:00

Subject: Counterfeit medicines supplier sentenced

A woman who supplied counterfeit prescription drugs to the UK was sentenced to two and a half years at Croydon Crown Court today.

Shazia Amjad, 39, of Uxbridge, was arrested as part of a joint investigation between the Medicines and Healthcare products Regulatory Agency (MHRA) and City of London Police.

Enforcement officers found counterfeit prescription drugs worth over £250,000, including more than 50,000 units of Ephedrine and a selection of slimming pills, erectile dysfunction pills, painkillers and anabolic steroids, when they searched Amjad’s address in November 2006.

In addition, officers found twelve passports hidden inside a suitcase. A total of 30 bank and visa cards were also recovered during the search. Officers discovered that the drugs originated in Pakistan and were mailed over to Amjad, who was paid in cash. The money was then credited to a bank account in the name of Reena Khan, a pseudonym used in one of the false passports

The size of the problem

• WHO estimates that 5-10% of global medicines are counterfeit, costing the industry up to €32 billion a year

• Annual growth of counterfeit medicines will outstrip that of legitimate medicines worldwide through 2010

• In 2004, counterfeiting was a €25.9 billion business projected to grow 13 percent year-over-year through 2010

• “The untrained eye wouldn’t distinguish the difference. Some of them contain active ingredients; some contain no ingredients; some lighter ingredients; and some toxic ingredients”

Definition

Good Distribution Practice (GDP) is that

part of quality assurance which ensures

that products are consistently stored,

transported and handled under suitable

condition as required by the marketing

authorisation (MA) or product specification

GDP – The Aim

• To get the product, manufactured under GMP to

the pharmacists and thereby to the end user in a

manner that ensures the integrity of the product

• Parties to GDP:

– The manufacturer

– The transporters

– The wholesale distributor

(and their transporters)

– The pharmacies

GDP – The Aim

• Integrity meaning two things:

– Lack of tampering / prevent counterfeiting

opportunities

• Reconciliation of quantities

• Tamper evident seals on individual units and on boxes

• Visual inspection

• Relabeling activities

– Safety and Efficacy (continuation of GMP)

• Storage and distribution temperatures and times

• Relabeling activities

Pharma Supply Chain

Raw

Material

Supply

Production Warehouse Transport DistributionEnd

use

Manufacturer Wholesaler

GMP GDP

Main activities of a Distributor

• Purchasing of medicinal Products– Manufacturers

– Wholesalers

• Warehousing– Acceptance

– Storage • Quarantine

• Release

• Customer call service– Picking

– Packaging

– Transport

– Delivery to authorized customers

• Handling of Returns

• Handling of Rejected products

• Relabeling activities

EU Regulations

– Directive 2004/93/EC laying down the principles and guidelines of good manufacturing practice of medicinal products for human use

– Directive 2001/83/EC, Title VII, on the wholesale distribution of medicinal products for human use.

– Directive 2005/28/EC on the requirements for authorisation of the manufacture or importation of clinical trial materials

– Guidelines on good distribution practice of medicinal products for human use (94/C 63/03)

The Legal Basis - EU

The Legal Basis - EU

The Legal Basis – EU

Concept paper to adopt WHO?

The legal basis - USA

• No specific GDP regulations

• Is apparently covered by state and

interstate laws rather than FDA regulated

• USP has chapter <1079>

Good Storage and Shipping Practices

in the general information chapters

WHO

TOC

Counterfeit Medicine - Definition

• Medicine deliberately and fraudulently mislabelled with respect to identity and/or source

• Can apply to branded and generic products

• May include product with:

– correct ingredients

– wrong ingredients

– without active ingredients

– with the quantity of active ingredients outside the product specification

– with fake packaging

– (too much active ingredient – less likely)

EU Legislation Under

Consideration

• A legal basis for the Commission to render obligatory specific safety-features on the packaging for prescription medicines.

• An extension of certain rules for wholesalers to other economic actors in the distribution chain who are involved in the transactions (for example, by auctioning products) without actually handling the products.

• Obligatory audits of distributors and harmonised rules for official inspections. Moreover, compliant wholesalers would be listed in a European database to enhance transparency of reliable traders.

• Strengthened requirements for importations of API if it is established that the regulatory framework in the respective third country does not ensure a comparable level of protection of human health for products exported to the EU

• Audits and notification of economic actors handling API in the EU

US Legislation Under Consideration

FDA Globalization Act of 2008

• Expands powers of FDA to impound and

DESTROY adulterated products at ports of

entry

• Requires mandatory registration of foreign

facilities

• Requires inspections at same frequency

as for domestic suppliers

What can I do?

• Training should include the topic of product security as well as aspects of product identification and measures taken to avoid introduction of counterfeit medicines into the supply chain

• Organizations in charge of pharmaceutical distribution must include in their existing security features, appropriate measure to prevent intruders entering their warehouses and to make known the presence of same, should they breach the existing security measures

• A record of all training should be kept

WHO guide on GDP (under revision)

What can I do?

• The quality system should include provisions that the holder of the marketing authorization, labelled entity (if different from manufacturer) the appropriate national and/or international regulatory bodies, as well as other relevant competent authorities, should be informed immediately in case of confirmed or suspected counterfeit medical products

• Such products have to be stored in a secure segregated area and have to be clearly identified to prevent further distribution or sale

WHO GDP

What Can I do?

• All parties involved in the distribution of pharmaceutical products should share responsibility for the quality and safety of products to ensure that they are fit for their intended use

• There should be a procedure in place that describes pedigree documentation as well as the visual and/or analytical identification of potential counterfeit products

WHO GDP Guide

What Can I do?

• Defined procedures for e-commerce and systems in place to ensure traceability and confidence in product quality. The sale of medicines via the Internet should be limited to registered and authorized mail order pharmacies and other legal entities only

• 6.6 Authorized procurement and release proceduresfor all administrative and technical operations performed should be in place, to ensure that appropriate products are sourced from approved suppliers and distributed by approved entities. There should be a written procedure in place to ensure and document traceability of products received and distributed based on batch numbers.

• 6.7 All entities in the supply chain should be traceable with written procedures and records to ensure traceability of distributed products

What Can I do?

6.9 To avoid penetration of counterfeits into the supply chain pedigree procedures and records should be developed for tracking and tracing of material and product. Each supplier should maintain and provide pedigree records to the next recipient in the supply chain ending with the final recipient before purchase/use by end-user (usually the patient)

6.10 Seal control programs for transit shipment: seals issued in a tracked and sequential manner, seals are intact and numbers verified during transit and upon receiptWritten procedures for the control of incoming materials including a plausibility check: might the products be counterfeit?

6.11 Establish measures to ensure that pharmaceutical products have. a form of documentation that can be used to permit traceability of the products throughout distribution channels from the manufacturer/importer to the retailer

Who is responsible for maintaining product

quality in the supply chain?

– The marketing authorisation holder

– The manufacturer and the Qualified Person

– The distributor and the Responsible Person

– The delivery driver

– The pharmacy and hospital (where relevant)

– The patient

– Everybody involved in the chain!

Duties of the Responsible Person

• To ensure provisions of licence are met

• To ensure operations are carried out in accordance with GDP

• To ensure an adequate quality system is established and maintained

• To oversee audit of the quality system and to carry out independent audits

• To ensure that adequate records are maintained

• To ensure that all personnel are trained

• To ensure full and prompt co-operation with MA holders in the event of recalls

EU GDP Regulations: Principle

• The Community pharmaceutical industry

operates at a high level of quality assurance,

achieving its pharmaceutical quality objectives

by observing Good Manufacturing Practice to

manufacture medicinal products which must

then be authorised for marketing

• This policy ensures that products released for

distribution are of the appropriate quality

EU GDP Regulations: Principle

• This level of quality should be maintained

throughout the distribution network so that

authorised medicinal products are

distributed to retail pharmacists and other

persons entitled to sell medicinal products

to the general public without any alteration

of their properties

EU GDP Regulations: Principle

• The concept of Quality Management in the

pharmaceutical industry is described in Chapter

I of the Community Guide to Good

Manufacturing Practice for medicinal products

and should be considered when relevant for the

distribution of medicinal products

• The general concepts of quality management

and quality systems are described in the CEN

standards (series 29 000) = ISO 9000

EU GDP Regulations: Principle

The quality system operated by distributors (wholesalers) of medicinal products should ensure that:

• medicinal products are authorised in accordance with Community legislation

• storage conditions are observed at all times, including during transportation

• contamination from or of other products is avoided

• an adequate turnover of the stored medicinal products takes place

• products are stored in appropriately safe and secure areas

EU GDP Regulations: Principle

• The quality system should ensure that the

right products are delivered to the right

addressee within a satisfactory time period

• A tracing system should enable any faulty

product to be found

• There should be an effective recall

procedure

Quality Management

Quality Management - Principle

• To achieve the quality objective reliably there must be a comprehensively designed and correctly implemented system of Quality Assurance incorporating:– Good Manufacturing Practice

– Quality Control and

– Quality Risk Management

• It should be fully documented and its effectiveness monitored

• All parts of the Quality Assurance system should be adequately resourced with competent personnel and

• suitable and sufficient premises, equipment and facilities

• MUST have a Quality Policy

Premises and Equipment

• Premises and equipment should be suitable and

adequate to ensure proper conservation and

distribution of medicinal products.

• Receiving Area

– Receiving bays should protect deliveries from bad

weather during unloading.

– The reception area should be separate from the

storage area.

• Monitoring devices should be calibrated

• Equipment should be validated

Typical Equipment

• Heating Ventilation Air Conditioning

(HVAC)

• Refrigerators

• Temperature/Humidity monitoring system

• Alarm system

• Generator

• Computerized systems

Equipment

• Critical equipment should be validated

• Measuring devices should be calibrated according to a written procedure

• A procedure for Preventive maintenance should be followed

• Log books should be kept for or critical equipment recording, as appropriate, any validations, calibrations, maintenance, cleaning or repair operations, including the dates and identity of people who carried these operations out.

• Any change in critical equipment should be subjected to change control procedure

Storage Practice

Storage

• Medicinal products should normally be stored apart from other goods and under the conditions specified by the manufacturer.

• Storage areas should be clean and dry andmaintained within acceptable temperature limits.

• Where special storage conditions are requiredon the label (e.g. temperature, relative humidity),these should be provided, checked, monitoredand recorded.

Storage

• Storage areas should provide adequate

lighting to enable all operations to be

carried out accurately and safely.

• Products should be stored off the floor and

suitably spaced to permit cleaning and

inspection.

• Pallets should be kept in a good state of

cleanliness and repair.

Storage

• Different products, and/or different batches

of the same product should be stored on

different pallets

• When upright orientation of storage is

signed products should be stored in

accordance

Storage

• A written cleaning program should be availableindicating the frequency of cleaning and themethods to be used to clean the premises andstorage areas.

• There should also be a written program for pestcontrol. The pest-control agents used should besafe, and there should be no risk ofcontamination of the materials andpharmaceutical products.

• There should be appropriate procedures for theclean up of any spillage to ensure completeremoval of any risk of contamination.

Storage

• Physical or Logistical (validated computerized

system with barcode) segregation

– Quarantined

– Released

– Rejected

– Returned

– Recalled

products

Storage

• Where quarantine status is ensured by

storage in separate areas, these areas

must be clearly marked and their access

restricted to authorized personnel

• Any system replacing physical quarantine

should provide equivalent security

• For example, computerized systems can

be used, provided that they are validated

Storage

• Physical or other equivalent validated (e.g.

electronic) segregation should be provided

for the storage of rejected, expired,

recalled or returned materials or products.

The materials or products, and areas

concerned should be appropriately

identified.

Storage

• Narcotics as well as substances

presenting special risks of abuse should

be stored in a dedicated area that is

subject to appropriate additional safety

and security measures.

Storage

• Products should be handled and stored in such

a manner as to prevent contamination, mix-ups

and cross-contamination.

• Products should be stored in conditions which

assure that their quality is maintained, and stock

should be appropriately rotated. The “first

expired/first out” (FEFO) principle should be

followed.

Receipt of incoming

pharmaceutical products • Medicinal products subject to specific storage measures

should be immediately identified and stored in accordance with written instructions and with relevant legislative provisions.

• On receipt, each incoming delivery should be checked against the relevant purchase order and each container physically verified, e.g. by the label description, batch number, type of material or pharmaceutical product and quantity.

• The consignment should be examined and if necessary, should be subdivided according to the supplier’s batch number should the delivery comprise more than one batch.

Receipt of incoming

pharmaceutical products• Each box/pallet should be carefully inspected for

possible contamination, tampering and damage. Medicinal products with broken seals, damaged packaging, or suspected of possible contamination should be withdrawn from saleable stock, and if not immediately destroyed, they should be kept in a clearly separated area so that they cannot be sold in error or contaminate other goods.

• When required, samples should be taken only by appropriately trained and qualified personnel and in strict accordance with written sampling instructions. Containers from which samples have been taken should be labelled accordingly.

Receipt of incoming

pharmaceutical products

• Following sampling, the goods should be subject to quarantine. Batch segregation should be maintained during quarantine and all subsequent storage.

• Products should remain in quarantine until an authorized release or rejection is obtained.

• Measures should be taken to ensure that rejected products cannot be used. They should be stored separately from other products while awaiting destruction or return to the supplier.

Stock rotation and control

• Periodic stock reconciliation should be performed by comparing the actual and recorded stocks.

• All significant stock discrepancies should be investigated

• All stocks should be checked regularly forobsolete and out-dated products. All dueprecautions should be observed to preventthe issue of outdated products.

Picking

• Picking of medicinal products for delivery

should be performed in accordance with

approved procedures and records should

be maintained.

• Records should allow tracability of

products in case of recall

Deliveries to Customers

• Deliveries should be made only to other

authorised wholesalers or authorised

pharmacies

• For all supplies a document must be enclosed,

making it possible to ascertain the date, the

name and pharmaceutical form of the medicinal

product, the quantity supplied, the name and

address of the supplier and addressee.

.

Good Transportation Practice

Transport

• Medicinal products should be transported in

such a way that :

a) their identification is not lost;

b) they do not contaminate, and are not contaminated

by, other products or materials;

c) adequate precautions are taken against spillage,

breakage or theft;

d) they are secure and not subjected to unacceptable

degrees of heat, cold, light, moisture or other adverse

influence, nor to attack by microorganisms or pests.

Transport

• Medicinal products requiring controlled temperature storage should be transported by appropriately specialised means.

• Special care should be exercised when using ice in cold chains. It must be ensured that the material or product does not come in into contact with ice, as this may adversely affect the product quality, e.g. by freezing.

• Where appropriate, the use of devices to monitor conditions such as temperature during transportation is recommended. Monitoring records should be available for review.

Returned Products

• Returned goods should be handled in accordance with approved procedures and records should be maintained.

• Non-defective medicinal products which have been returned should be kept apart from saleable stock

• to prevent redistribution until a decision has been reached regarding their disposal.

• Products which have left the care of the wholesaler, should only be returned to saleable stock if:

Returned Products

a) the goods are in their original unopened containers and in good condition;

b) it is known that the goods have been stored and handled under proper conditions;

c) the remaining shelf life period is acceptable;

d) they have been examined and assessed by a person authorised to do so. This assessment should take into account the nature of the product, any special storage conditions it requires, and the time elapsed since it was issued. Special attention should be given to products requiring special storage conditions. As necessary, advice should be sought from the holder of the marketing authorisation or the Qualified Person of the manufacturer of the product.

Returned Products

• Records of returns should be kept. The

responsible person should formally

release goods to be returned to stock.

• Products returned to saleable stock should

be placed such that the "first expired first

out“ system operates effectively.

Temperature mapping

• Initial validation

– Empty state

– Maximum loaded state

– Cold season

– Hot season

• Revalidation

– Warehouse -Following significant changes

– Refrigerators – Every year (loading as is)

Temperature Monitoring

• Sensors of the monitoring system should be located at the worst case areas identified by the temperature mapping

• Temperature records should be reviewed and confirmed and signed by an authorised person on a daily basis.

• Records should be kept for at lease 6 years (One year beyond products’ expiry date)

Temperature Monitoring

• Deviations should be investigated and

corrective actions should be implemented

• MA Holder may by notified in accordance

to the quality agreement.

Cold Chain

Cold Storage

• Biological products must be protected from

freezing; even a brief period at sub-zero

temperatures may irreversibly denature

the protein, leading to a loss of efficacy.

• There are also products such as emulsion

systems and solutions of sparingly soluble

components which may become physically

unstable at sub-zero temperatures.

Cold Storage

• Before setting up a cold storage facility or

transport system, or before taking on a

new range of products, it may be useful for

distributors to carry out a risk analysis to

establish a list of high, medium and low

risk products and to make appropriate

arrangements for their handling.

Cold Storage

• Domestic refrigerators are generally not suitable

for high risk products because they may not

have the precise electronic control necessary to

maintain the temperature within the range

5±3ºC.

• Refrigerators are available which are specially

designed for the storage of medicinal products

and their use is to be encouraged for all

products requiring storage between 2°C and

8°C.

Cold Storage

• Care should be exercised when placing goods in

domestic units. If they are placed next to, or

allowed to come into contact with the chiller

plate or coil, their temperature may fall below the

minimum recommended by the manufacturer.

• Sufficient space should be maintained between

the goods and the internal surfaces of the unit to

permit adequate air circulation

Cold Storage

• The probe may be placed within the load (or within a suitable buffer) to record the load rather than the air temperature

• The device should be calibrated annually against a certificated thermometer.

• The unit should have an auto-defrost facility and the temperature within the unit should not be affected during the defrost cycle.

• The correct functioning of the alarm should be checked annually at the high and low set points.

Cold Storage

• Refrigerators should be sited in an environment

where the ambient temperature does not affect

the temperature control within the unit.

• For example, it should not be sited in an

unheated loading bay, or in an area of potential

heat gain.

• Most refrigerators will function efficiently in an

external environment of between 10°C to 32°C.

Cold Storage

• Condensate from chiller units should not

be collected inside the cold store in an

open vessel.

• All units, should be cleaned and

disinfected regularly to prevent mould

growth, and (as for all storage facilities)

goods should not be stored directly on the

floor.

EC GDPs: storage temperatures

– Products requiring controlled temperature storage

should be identified on receipt and stored in

accordance with written instructions

– Temperatures should be monitored and recorded

periodically. Records should be reviewed regularly

– Controlled temperature storage areas should be

equipped with temperature recorders. Control

should be adequate to maintain all parts of the area

within the specified temperature range

EC GDPs: shipping temperatures

– Medicines should be transported in such a way that they are secure and are not subjected to unacceptable degrees of heat and cold.

– Medicinal products requiring controlled temperature storage should also be transported by appropriately specialised means.

Why is MHRA concerned about

temperature control?

32% of all critical and major deficiencies

recorded by MHRA’s GDP inspectors

during 2005/2006 related to the control and

monitoring of storage and transportation

temperatures

Documentation and Records

• Documents, such as procedures, instructions, protocols and reports should be approved, signed and dated by appropriate and authorised persons.

• Documents should be regularly reviewed and kept up-to-date. When a document has been evised, systems should be operated to prevent inadvertent use of superseded documents.

• Documents should not be handwritten; although, where documents require the entry of data, these entries may be made in clear, legible, indelible handwriting. Sufficient space should be provided for such entries.

Documentation and Records

• Any alteration made to the entry on a document should be signed and dated; the alteration should permit the reading of the original information. Where appropriate, the reason for the alteration should be recorded.

• The records should be made or completed at the time each action is taken and in such a way that all significant activities are traceable.

• They should be retained for at least one year after the expiry date of the product.

Documentation and RecordsSOPs should cover activities such as

• Purchase

• Receipt

• Sampling

• Storage

• Release/Reject

• Picking

• Dispatch and transport

• Returns

• Destruction

• Re-labeling

– Security

– Computerized systems

and electronic data

– Maintenance and

Calibration

– Cleaning

– Pest Control

– Recall

– Complaints

– Self inspections

Re-labeling

• Re-labeling activities are subjected to

GMP requirements

Printed Materials Master File

• Printed Materials Master File should include

– Approved samples of the printed materials

– Serial number and edition of the printed materials

– Instructions for re-labeling

– Specifications of the printed materials

• Re-labeling procedure should be in accordance

with the instruction within the Master File

Re-labeling

.

• Before re-labeling operations are begun, steps should be taken to ensure that the work area is clean and free from any products, materials or documents previously used, if these are not required for the current operation. The line-clearance should be performed according to an appropriate check-list.

• All products and packaging materials to be used should be checked on delivery to the re-labeling department for quantity, identity and conformity with the re-labeling instructions.

Re-labeling

• Before re-labeling activities are begun employees should be trained in accordance to the product specific re-labeling instructions and training should be recorded

• Samples of labels/inserts should be attached to the re-labeling batch record

• Defected labels/inserts discovered along the process should be rejected and signed as rejected

• The process should be controlled by sampling and testing of re-labeled packages in predefined intervals

Re-labeling

• At the end of the process the amount of

the pre-labeled products, and printed

packaging materials and the number of

units produced should be reconciled.

• Any significant or unusual discrepancy

observed during reconciliation should be

• investigated and satisfactorily accounted

for before release.

Re-labeling

• Upon completion of a packaging operation, any

rejected printed material (and leftovers) should

be destroyed and the destruction recorded.

• A documented procedure should be followed if

printed materials are returned to stock.

• Re-labeling batch record should be reviewed

and approved by an authorised person.

• Re-labeling approval should be a perquisite for

release of the product.

Printed Materials Management

• Printed Materials should be purchased from qualified printers only.

• Incoming printed materials should be placed in quarantine and to be sampled according to a predefined sampling procedure.

• Samples should be tested for accurate text in accordance with the Master file, and for meeting specifications limits.

Printed Materials Management

• Testing results should be documented and if satisfactory the printed material should be released and removed to relesed printed materials area.

• Printed Materials should be stored in a designated area with limited access to authorised personnel in suitable conditions for preservation of the materials.

• Use of printed materials should follow FIFO principles

Complaints

• There should be a written procedure in place for the handling of complaints.

• A distinction should be made between complaints about a product or its packaging and those relating to distribution. In the case of a complaint about the quality of a product or its packaging the original manufacturer and/or marketing authorization holder should be informed as soon as possible.

• Any complaint concerning a material defect should be recorded and thoroughly investigated to identify the origin or reason for the complaint (e.g. repackaging procedure, warehousing procedures, etc.)..

• Where necessary, appropriate follow-up of corrective actions should be taken

Emergency Plan and Recalls

• An emergency plan for urgent recalls and a non-urgent recall procedure should be described in writing. A person should be designated as responsible for execution and co-ordination of recalls.

• Any recall operation should be recorded at the time it is carried out and records should be made available to the competent authorities.

• In order to ensure the efficacy of the emergency plan, the system of recording of deliveries should enable all destinees of a medicinal product to be immediately identified and contacted. In case of recall, wholesalers may decide to inform all their customers of the recall or only those having received the batch to be recalled.

Emergency Plan and Recalls

• In case of batch recall, all customers to whom the batch was distributed should be informed with the appropriate degree of urgency.

• . The recall message approved by the holder of the marketing authorisation, and, when appropriate, by the competent authorities, should indicate whether the recall should be carried out also at retail level.

• The message should request that the recalled products be removed immediately from the saleablestock and stored separately in a secure area until they are sent back according to the instructions of the holder of the marketing authorisation.

The Role of the Responsible

Pharmacist• Responsible Pharmacist is required by the

Israeli law

• The responsible pharmacist has the sole authority for release/reject products following batch release of MOH (in imported products) and as such should be independent of operations department

• The responsible pharmacist is the liaison person with MOH and with MA holders

• Responsible pharmacist normally plays an active role in the quality system in coordination with the quality assurance manager

Compliance issues: storage

– Temperature monitoring records

– Temperature mapping

– Alarm systems

– Response to out-of-specification (alarm) conditions

– Qualification/requalification

– Cleanliness

– Receipt of cold chain goods (time outside cold

store)

Compliance issues: transportation

– Monitoring devices and their location

– Temperature monitoring records

– Shipping containers

– Controlled use of cooling elements

– Uncertain audit trail

– Temperature mapping (vehicles)

– Contract transport and audit

Other issues

– Training - warehouse personnel, drivers, etc.

– Written procedures

– Calibration of temperature monitoring devices

– Returns of cold chain goods

– Representatives’ samples

– Maintenance of the cold chain of imports

– Maintenance of the cold chain to patient level

Calibration

– Manual and electronic recording devices used in

critical areas should be calibrated at least

annually against a traceable reference device

– Records should include pre- and post-calibration

readings and details of any adjustments made or

corrections to be applied

– Alarms should be checked at least annually for

correct functioning at the designated set points

Risk assessment: matters to consider

– Nature of the products (solids, semisolids, liquids)

– Labelled storage requirements and associated

warnings

– Sensitivity of product to extremes of temperature

– Likely period of exposure to temperatures outside

the labelled storage requirements

– Maximum and minimum temperatures that may be

experienced by the product

– Exposure to fluctuating temperatures

Risk assessment: matters to consider

– Number and nature of the stages in the chain

– Number of drop-off points in delivery chain

– MA holder’s advice (in writing)

– Scale of the operation

– Support available (service providers)

– Knowledge and experience of potential

contract acceptors

High risk products

– Products at risk from freezing:

• vaccines, insulins, biotech products, blood products

• those physically unstable, e.g. some emulsion

systems

– Products at risk from elevated temperatures

• those described above, and

• those chemically unstable at elevated

temperatures, e.g. chloramphenicol eye drops

• some semi-solids, e.g. fatty-based suppositories

UK top 10 critical/major GDP

deficiencies for 2005/2006

Description %

General storage - temperature control & monitoring 16.7

Unauthorised activity 9.6

Lack of or inadequate written procedures 8.8

Supplier status 7.9

Cold storage - temperature control & monitoring 7.9

Premises 7.0

Cold chain transportation 7.0

Quality management and duties of the Responsible Person 5.3

Segregation of unsaleable stock 3.5

Returns 3.5

Inspection finding: temperate storage

• Temperatures are not monitored in the general storage areas. A thermometer taken from one of the offices indicated a temperature of 35°C on the mezzanine floor at the time of inspection.

• The warehouse has not been temperature-mapped under extremes of external temperature to determine the hot and cold spots and the general temperature distribution

Inspection finding: cold storage

• A external monitoring station recorded an

out of temperature limit alarm in a

wholesale distributor’s 2-8°C cold room on

a Saturday evening. The company’s

Responsible Person was advised of this

shortly afterwards, but no corrective action

was taken until the following Monday, by

which time the temperature in the cold

room had risen to 25°C.

Inspection finding: cold chain transportation

• In general, cold chain products are not transported to customers under conditions that ensured that the labelled storage requirements of 2-8ºC are maintained

• The company has no knowledge of the temperatures that goods in transit might experience during extremes of external temperature

What happens when things go wrong?

– Risk to patients

– Expensive recalls

– Loss of confidence in the company

– Regulatory action

• suspension of manufacturing/distribution

authorisation

• compulsory variation of authorisation

• revocation of authorisation

• sanctions against the QP or RP

Challenges facing regulators

– Counterfeits

• non-legitimate supply chain

• legitimate supply chain

– Clones or copies

– Internet sale and advertising

What distributors should have in place

– A comprehensive quality management

system

– A process for continual quality improvement

– A cold chain distribution strategy

– A temperate chain distribution strategy

– A risk assessment programme

Quality Reviews

• CAPA system is an integral part of any

functional quality system

(Corrective and Preventive Actions)

• Periodic quality reviews at the

management level (means General

Manager or President) engages their

attention and allows for resources to be

diverted as needed

Quality Reviews

• Formal reviews should be performed

• Don’t focus on positive!!

• Highlight UNRESOLVED problems so that

management can provide the solutions

– We need 4 new refrigerated vans

– The warehouse cannot maintain the required

temperature profile in summer and summer is

approaching

– We need additional quarantine storage space

(provide figures)

Measures of Improvement

• Complaints (logistics AND quality):

– Reduction in number

– Reduction in severity

– Decreased response time

• Deviations (as above)

• Self-inspection / vendor audits

– Reduction in severity of findings

– Improved quality of responses

– Improved response time

Measures of Improvement- Reports

• Complaints

• Product Quality Review

• Critical Systems Review

• Deviations (planned or

not)

• Rejected Product

• Returns (Policy?)

• Goods Destruction

• Change Control

• Validation / Calibration

Status

• SOP Review

• Audits

• Training

CAPA Program

1. ID existing problems CA

– ID quality data sources

– analyze data

2. ID potential problems PA

– as above (but trends, SPC)

3. Challenge Data– complete, accurate, timely

4. Identify extent of problems

5. Failure investigation– Follow SOP; depth relative to

risk, root cause if possible, stop distribution

6. Appropriate Action Taken

7. Actions:– appropriate; verified /

validated, do notadversely affect product

8. Actions:– implemented

– documented

9. Information Transfer tothose responsible for– assuring product quality

– preventing quality problems

Program in place, Audit,

Management Involvement

What does the future hold

• ICH Q10 on Pharmaceutical Quality Systems:

Use quality risk management to develop a

product control strategy including rapid

analytical test methods

• Product Control Strategy:

A planned set of controls, derived from

current product and process understanding,

that assures process performance and

product quality – includes test methods

In conclusion

• GDP regulations: EU and WHO, USP

• FDA appear to be lagging behind but ISO is certainly a good place to start

• Quality System MUST be in place

• Would expect a Quality Manager who is familiar with EU GDP and USP requirements

• Need quality contracts in place (more of that later) and need to audit:– Your distributor

– Their distributor

– Their print houses (or rely on their audits)

Risks to Pharmaceuticals during

storage & distribution• Mix up of products

• Mix up of batches

• Contamination

• High humidity

• High temperatures

• Excess of light

• Freezing

• Pests

• Filth

• Non secure

• Distribution of non released products

• Use of unsuitable vehicles

• Damage to products

• Loss of products

• Delay in supply

• Supply of wrong products

• Substitution with counterfeit product

• Distribution of expired / damaged products

Risks to Pharmaceuticals in transit Shipment of wrong

product

Shipment to wrong destination

Shipment by wrong carrier

Inappropriate handling/loading

Damage in transit

Loss in transit

Delays in transit

Temperature deviations

Unauthorised access

Use of unapproved or

inappropriate equipment

Mixing of batches

Breakdown of pallets

Co-loading with

inappropriate cargo

Late delivery

Untrained

drivers/administrators

Poor record keeping

Substitution by counterfeit

products